Striatal and Extrastriatal Dopaminergic Neurotransmission to Schizophrenia The dopamine (DA) hypothesis of schizophrenia, formulated more than 30 years ago, still lacks definitive experimental validation and must be modified to account for the diversity and complexity of DA transmission in cortical and subcortical regions of the brain. Using state-of the-art radio-tracer imaging techniques, this project will assess dopaminergic function in both cortex and striatum of patients with schizophrenia compared to healthy thalamus, and striatum but also, using a novel pharmacological approach, the synaptic levels of the neurotransmitter itself, i.e. dopamine. These studies will provide information never previously obtained in either schizophrenic or healthy subjects and will directly test theories of dopamine's involvement in the pathophysiology of psychosis. Using SPECT (single photon emission computed tomography) D2 receptor imaging in the striatum combined with an amphetamine challenge, we previously found that schizophrenic patients have an elevated release of dopamine and that transient increases in psychotic symptoms were correlated with the amount of DA receptors in thalamus and temporal cortex and by measuring baseline synaptic DA levels. D2 receptors will be imaged with an equilibrium paradigm using the high affinity tracer [123I]epidepride (EPID). Synaptic levels of DA will be assessed with a second [123I]EPID scan, obtained after DA depletion induced by two days treatment with the synthesis inhibitor alpha-methyl-paratyrosine (AMPT). We have shown that treatment of both baboons and healthy subjects with AMPT depletes DA levels, "unmasks" receptors which were occupied by the transmitter; and, thereby, increases radio-tracer binding to the D2 receptor. We hypothesize that patients with schizophrenia will show a dysregulated of cortical and subcortical DA transmission. Specifically, patients will show higher DA transmission in temporal cortex than striatum, which will be assessed as the % D2 receptors unmasked in temporal cortex compared to % D2 receptors unmasked in striatum. Furthermore, the comparison of schizophrenic patients and healthy subjects on scan 1 alone will provide new imaging data (not previously published) on the baseline levels of extrastriatal D2 receptors in this disorder.